Cancer chemotherapy causes marked cognitive impairment that involves deficits in learning & memory, attention, and executive functions. The best characterized genetic risk factor for chemotherapy induced cognitive impairment (CICI) is the E4 allele of APOE, which is also the strongest genetic risk factor for Alzheimer?s disease (AD). This commonality of risk provides a powerful opportunity to define mechanisms of the effects of APOE4 on cognitive dysfunction across conditions. We have developed a mouse model of APOE4-related CICI showing strong chemotherapy-induced cognitive effects in the APOE4 mice but not APOE3 mice, providing independent confirmation of this genetic risk in humans. We hypothesize that chemotherapy induces CNS damages related to APOE functions. We are testing specific mechanisms of APOE4-related vulnerability in four specific aims: Aim 1: Determine how chemotherapy affects pathogenic processes of Alzheimer?s disease. We will use a mouse model of amyloid influenced by the different APOE alleles (EFAD mice), to define mechanisms of chemotherapy on AD pathogenesis. We will expose cohorts of E3FAD and E4FAD mice to a chemotherapy regimen or vehicle control, and determine which AD pathological pathways are affected (A? levels, phospho-tau, microglial and astrocytic activation, neuronal and synaptic loss, and hippocampal atrophy). Aim 2: Define mechanisms of APOE4-related chemotherapy sensitivity in a non-AD model. The APOE4 knock-in mouse model allows testing for CNS alterations that may underlie CICI in cognitively healthy individuals. We will test CNS mechanisms already identified in relation to the APOE4 genotype for exacerbation after chemotherapy, including: inflammation; neurogenesis; DNA damage; glial senescence; blood brain barrier breakdown; and oxidative damage. Aim 3: Identify specific chemotherapies associated with lower risks of cognitive impairment. We will use our sensitive and reproducible APOE4 mouse model to test whether some cancer chemotherapeutic approaches are safer than others. We will treat the susceptible APOE4 mice with four of the common cancer chemotherapies with different mechanisms of action. Aim 4: Test therapeutic approaches to prevention of chemotherapy-induced cognitive impairments. Identification of APOE-related mechanisms allows the targeted identification of preventative approaches. We initially will test an agent for increasing lipidated APOE levels (bexarotene), and an anti- inflammatory agent (an antagonist of the receptor for advance glycation endproducts (RAGE)). Together, these Aims will identify mechanisms underlying the risk of CICI in the large portion of the population carrying the APOE4 allele. In addition, the acute nature for the onset of CICI allows a more controlled approach for studying the negative effects of APOE4 in vivo, compared to only studying gradual processes of aging and neurodegeneration. Findings can be easily translated to clinical situations in terms of identifying at risk individuals and in terms of identifying new APOE4-related biomarkers of cognitive impairment.